The safety profile of direct oral anticoagulants

Direct oral anticoagulants (DOACs), also known as New Oral Anticoagulants (NAOs), have for the first time provided a therapeutic alternative to vitamin K antagonists (VKAs), of which warfarin is the prototype, indicating neither inferiority nor superiority in the prevention of stroke in case of non-valvular atrial fibrillation.
The aim of this article is to compare the safety profile of these anticoagulants with warfarin. To this end, a study was conducted using Vigibase, the World Health Organization database that collects reports of suspected adverse drug reactions worldwide.¹

The study

The reports concerning patients with non-valvular atrial fibrillation who reported DOACs or warfarin as a suspicious or interacting drug were selected within the database. For the statistical analysis of the drug-reaction pairs, the Reporting Odds Ratio (ROR) was used with a 95% confidence interval as a measure of disproportionality.
In the database, 115,412 reports were collected that showed DOACs or warfarin as suspected drugs, of which 32,972 were patients with non-valvular atrial fibrillation. Among these, 3,230 drug-reaction pairs were selected, of which 204 had a ROR of >1, an indicator of a positive association between DOACs and adverse reaction under examination with respect to warfarin.
As highlighted by several clinical trials reported in the literature, this study also showed a disproportionality for the direct oral anticoagulant pair and gastrointestinal haemorrhage ROR 1.60 (95% CI 1.47-1.75). Specifically, both dabigatran ROR 1.71 (95% CI 1.56-1.87) and rivaroxaban ROR 1.38 (95% CI 1.24-1.55), unlike apixaban, showed a positive ROR compared to warfarin. Conversely, a ROR of <1 (ROR 0.31, 95% CI 0.28-0.34) emerged for cerebral haemorrhages, again confirming what was reported by clinical trials and other post-marketing studies.
With regard to hepatic toxicity, there were several drug-reaction pairs that showed a positive association, especially in relation to rivaroxaban, a drug metabolised mainly in the liver. The assessment of the safety profile at the renal level is noteworthy since DOACs, unlike warfarin, are excreted in different percentages by the renal route. Among the adverse reactions associated with DOACs we find nephrolithiasis (ROR 2.06, 95% CI 1.07-3.98), renal insufficiency (ROR 2.91, 95% CI 2.09-4.05) and bladder bleeding (ROR 3.69, 95% CI 1.76-7.70). Monitoring of renal function should be performed at the beginning and during treatment with anticoagulant drugs, especially with direct anticoagulants. In fact, alteration of renal function causes variation in the drug plasma concentration, exposing the individual to possible adverse reactions, including serious ones.
In case of renal insufficiency, it is advisable to evaluate the degree and consequently to reduce the dosage of the anticoagulant drug. Each patient needs a careful evaluation and the treatment must be calibrated accordingly. To facilitate this task in clinical practice, several guidelines are available, such as those published by the Emilia-Romagna regional authority, updated in March 2018², which offer support in patient management.

In practice

Overall, these drugs have provided an alternative to warfarin for the first time in terms of efficacy and safety in patients with atrial fibrillation. However, more attention must be paid to the management of individual patient treatment by evaluating the risk-benefit ratio. Pharmacovigilance studies based on spontaneous reporting make it possible to find essential information for the analysis of the safety profile of drugs in actual clinical practice. The analysis of the safety profile of DOACs compared to warfarin has aided the detection of positive associations with adverse reactions already identified in clinical trials and to identify new indications that warrant further research. On the other hand, an increased risk of gastrointestinal bleeding and a reduction in the risk of cerebral haemorrhages appear to be the two most distinctive features of treatment with new anticoagulants. The study also found that DOACs are not interchangeable but careful treatment contextualisation must be made, taking into account the patient’s condition. At the moment apixaban appears to be the anticoagulant with the most favourable safety profile in the class of direct anticoagulants, although it was also the last to enter the market.